Autophagy

Bhogal, Ricky H.; Weston, Chris J.; Curbishley, Stuart M.; Adams, David H.; Afford, Simon C.

doi:10.4161/auto.19012

Cited by 79 publications

(47 citation statements)

References 42 publications

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“…Therefore, the elimination of a few unstable and potentially dangerous mitochondria by autophagy preserves cellular integrity and maintains cellular homeostasis [39]. Recent studies have shown that autophagy plays a protective role against the mitochondrial dysfunction and apoptosis induced by oxidative stress in hepatocytes [40,42]. Our data revealed that Baf.…”

Section: Discussionmentioning

confidence: 59%

“…Autophagy is a lysosome-mediated degradation process that regulates the turnover of long-lived proteins and eliminates dysfunctional organelles, including mitochondria, to preserve basal cellular and tissue homeostasis [5,39,40]. The autophagy pathway begins with the formation of double-membrane vesicles also known as autophagosomes, and LC3-II is a representative protein component of the autophagosomal membrane.…”

Section: Discussionmentioning

confidence: 99%

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Eupatilin induces Sestrin2-dependent autophagy to prevent oxidative stress

Jegal

Park

et al. 2016

Apoptosis

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Eupatilin (5,7-dihydroxy-3,4,6-trimethoxyflavone) has many pharmacological activities including anti-inflammation, anti-oxidant and anti-cancer effects. Autophagy is the basic cellular machinery involving the digestion of damaged cellular components. In the present study, we investigated the protection effects of eupatilin against arachidonic acid (AA) and iron-induced oxidative stress in HepG2 cells and tried to elucidate the molecular mechanisms responsible. Eupatilin increased cell viability against AA + iron in a concentration-dependent manner and prevented mitochondrial dysfunction and reactive oxygen species (ROS) production. In addition, AA + iron increased the levels of pro-apoptotic proteins and these changes were prevented by eupatilin. Eupatilin also induced autophagy, as evidenced by the accumulation of microtubule-associated protein 1 light chain3-II and the detection of autophagic vacuoles. Furthermore, the protective effects of eupatilin on mitochondrial dysfunction and ROS production were significantly abolished by autophagy inhibitors. Eupatilin also increased the mRNA level of sestrin-2 and its promoter-driven reporter gene activity, which resulted in the up-regulation of sestrin-2 protein. Finally, gene silencing using sestrin-2 siRNA and the ectopic expression of recombinant adenoviral sestrin-2 indicated that sestrin-2 induction by eupatilin was required for autophagy-mediated cytoprotection against AA + iron. Our results suggest that eupatilin activates sestrin-2-dependent autophagy, thereby preventing oxidative stress induced by AA + iron.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Eupatilin induces Sestrin2-dependent autophagy to prevent oxidative stress

Jegal

Park

et al. 2016

Apoptosis

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“…Damaged organelles participating in ROS generation, including mitochondria, are sequestrated and removed by the autophagic process, and autophagy plays a role in suppression of ROS generation and subsequent apoptosis [63]. Autophagy prevents hepatocyte apoptosis or necrosis under conditions of hypoxia-induced oxidative stress [54,56,64,65]. Considering these facts, it seems that the formation of mitochondrial autophagosomes in hepatocytes during warm ischemia suggested that the autophagy system plays a role in protecting hepatocytes from hypoxic injury.…”

Section: Discussionmentioning

confidence: 99%

The ultrastructural characteristics of porcine hepatocytes donated after cardiac death and preserved with warm machine perfusion preservation

et al. 2017

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The effects of warm machine perfusion preservation of liver grafts donated after cardiac death on the intracellular three-dimensional ultrastructure of the organelles in hepatocytes remain unclear. Here we analyzed comparatively the ultrastructure of the endomembrane systems in porcine hepatocytes under warm ischemia and successive hypothermic and midthermic machine perfusion preservation, a type of the warm machine perfusion. Porcine liver grafts which had a warm ischemia time of 60 minutes were perfused for 4 hours with modified University of Wisconsin gluconate solution. Group A grafts were preserved with hypothermic machine perfusion preservation at 8°C constantly for 4 hours. Group B grafts were preserved with rewarming up to 22°C by warm machine perfusion preservation for 4 hours. An analysis of hepatocytes after 60 minutes of warm ischemia by scanning electron microscope revealed the appearance of abnormal vacuoles and invagination of mitochondria. In the hepatocytes preserved by subsequent hypothermic machine perfusion preservation, strongly swollen mitochondria were observed. In contrast, the warm machine perfusion preservation could preserve the functional appearance of mitochondria in hepatocytes. Furthermore, abundant vacuoles and membranous structures sequestrating cellular organelles like autophagic vacuoles were frequently observed in hepatocytes after warm machine perfusion preservation. In conclusion, the ultrastructure of the endomembrane systems in the hepatocytes of liver grafts changed in accordance with the temperature conditions of machine perfusion preservation. In addition, temperature condition of the machine perfusion preservation may also affect the condition of the hepatic graft attributed to autophagy systems, and consequently alleviate the damage of the hepatocytes.

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“…Bhogal et al showed that inhibition of autophagy using 3-methyladenine increases apoptosis in primary human hepatocytes under oxidative stress (56). More recently, work by Yun et al suggests that there is an impaired autophagy response after hepatic I/R, where pharmacologic inhibition of autophagy further exacerbates injury (57).…”

Section: Discussionmentioning

confidence: 99%

Sirtuin 1 Stimulation Attenuates Ischemic Liver Injury and Enhances Mitochondrial Recovery and Autophagy

Khader¹,

Yang²,

Godwin

et al. 2016

Critical Care Medicine

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Objective Hepatic ischemia-reperfusion (I/R) is a major clinical problem with limited treatment options. The pathophysiology of hepatic I/R is characterized by mitochondrial dysfunction and cellular energy deficits. Sirtuin 1 (Sirt1) is an energy-sensing enzyme known to modulate mitochondrial biogenesis. We hypothesized that pharmacologic activation of Sirt1 is protective after hepatic I/R injury. Design Animal study. Setting University-based experimental laboratory. Subjects Wild-type C57BL/6 mice. Interventions C57BL/6 mice were subjected to 60-min partial hepatic I/R and post-treated with Sirt1 activator, SRT1720 (20 mg/kg), or vehicle. Blood and liver were collected at 24 h after I/R for analyses of hepatic injury, ATP levels, mitochondrial mass, autophagy, inflammation, and oxidative stress. H4IIE hepatoma cells and rat primary hepatocytes were incubated with oxyrase to induce hypoxia followed by reoxygenation (H/R) in the presence or absence of SRT1720 for assessment of mitochondrial mass, mitochondrial membrane potential, and autophagy. Measurements and Main Results SRT1720 restored the reduction in mitochondrial mass, enhanced autophagy, and preserved ATP levels in the liver after I/R, which was associated with a decrease in I/R-induced hepatic injury, apoptosis, and necrosis. I/R-induced inflammation was also significantly reduced by SRT1720 as measured by systemic and hepatic cytokine and chemokine levels as well as a decrease in neutrophil infiltration to the liver. Further, oxidative stress was markedly attenuated in the SRT1720-treated mice, compared to the vehicle. SRT1720 treatment increased ATP levels and survival of cultured hepatocytes after H/R. SRT1720 not only increased the mitochondrial mass but also increased mitochondrial membrane potential per cell in cultured hepatocytes after H/R. Moreover, SRT1720 prevented the H/R-induced mitochondrial depolarization and resulted in an enhancement of autophagy in cultured hepatocytes after H/R. Conclusions Pharmacologic stimulation of Sirt1 attenuates liver injury after hepatic I/R by restoring mitochondrial mass and membrane potential, which is associated with the enhancement of autophagy.

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Autophagy

Cited by 79 publications

References 42 publications

Eupatilin induces Sestrin2-dependent autophagy to prevent oxidative stress

Eupatilin induces Sestrin2-dependent autophagy to prevent oxidative stress

The ultrastructural characteristics of porcine hepatocytes donated after cardiac death and preserved with warm machine perfusion preservation

Sirtuin 1 Stimulation Attenuates Ischemic Liver Injury and Enhances Mitochondrial Recovery and Autophagy

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